Stroke is the leading cause of disability in the US and with heart disease, the leading cause of death. The risk for stroke with consequent functional disability is increased with age, and in women this risk is elevated after the menopause. Paradoxically, hormone therapy at menopause increases the risk for stroke. Animal models of stroke confirm that stroke severity is worse in aged animals as compared to younger animals. In middle age, our recent data shows that female rats sustain a greater degree of tissue damage in the cortex and striatum as compared to younger females. Middle aged males, on the other hand, do not differ significantly from younger males in the extent of cortical infarction. This age difference in cortical cell loss is also paralleled by functional changes in astrocytes, a specific brain support cell. Astrocytes play a key role in normal and pathological conditions. Following stroke, astrocytes are rapidly mobilized to the peri-infarct area, detoxify the injured brain via glutamate uptake and fluid efflux and secrete growth factors known to promote angiogenesis and neuronal survival and neurogenesis. Astrocytes culled from the ischemic cortex of middle aged female rats show profound loss of protective functions including a reduced ability to sequester glutamate, decreased growth factor release, increased release of chemokines and increased ability to recruit leukocytes. These changes are consistent with increased infarct volume observed in older females. Hence in this proposal we will determine age and sex-specific epigenomic changes in astrocytes obtained from the ischemic cortex, to determine critical translational and transcriptional modulators.
In Specific Aim 1 we will determine age-related changes in the expression of small non-coding RNA. MicroRNA, a key translation regulatory element, regulates large gene networks, and have been shown to play a central role in cell senescence and injury (stroke).
In Specific Aim 2 we will determine age-related changes in DNA and histone methlyation patterns. Methylation patterns of specific leucines associated with activation (H3K4me3 and H3K9ac) or repression (H3K9me3 and H3K27me3) of gene transcription will be targeted. These complementary approaches will allow us to develop a molecular fingerprint of the aging astrocyte. Finally, in Specific Aim 3, select molecular targets will be manipulated using (1) miRNA mimetics or antagomirs and (2) demethylases to reverse age-specific patterns in astrocytes. Data gathered from these studies is expected to aid in the eventual identification of epigenomic changes that predict disease severity and facilitate discovery of therapeutic targets.
The risk and disability associated with stroke increases with age. In order to develop more effective therapies for this disease, this application will focus on age-related changes in a specific brain cell called the astrocyte. Our studies using an animal model show that middle-aged females sustain more brain damage after stroke than younger females and this is associated with functional changes in the neuroprotective ability of astrocytes. We will seek to understand global age-related changes in this cell type so as to develop markers for disease severity as well as new therapeutic targets.
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